Saturday, December 8, 2012

The Post-Chloroquine Era

Figure 1. Chinchona bark

containing quinine (9).

by FC

Nothing in this world seems as interminable
as the race of humans versus pathogens. The moment we celebrate a success
against an organism that plagues our existence we are served another. Just when
we find a weapon to combat the pathogen, it changes its attack. This pattern is
no exception for Plasmodium falciparum.
Earning the title as one of the most deadly infectious parasites, its
widespread occurrence is a health and economic issue (4). For some time the
advent of chloroquine allowed us a triumph, but today a grimmer picture is
portrayed. Not only has chloroquine use become obsolete, the alternatives are
limited by cost and supply (4,7). Unless serious international investment and
multinational collaboration takes place, the rising health and economic burden
of malaria will continue unabated (4).

When chloroquine came
onto the scene in 1934, it addressed the demand for a quinine substitute (7,8).
Found in Chinchona tree bark, quinine was used for an estimated 278 years
before reports of P. falciparum
resistance began to surface around 1910 (5,8). Efforts to synthesize a new
antimalarial surged in the early 20th century, producing the worlds’
most widely used antimalarial. However, this advancement did not occur without
setbacks. When chloroquine was first synthesized it was dismissed on the
assumption that it was too toxic. Its resurrection was triggered only when the
Japanese cut off the world supply of quinine in World War II, and by 1946 studies
by American researchers observed its utility as a powerful antimalarial (3).

Figure 3. World map highlighting regions with

a chloroquine failure rate of 10% or more (10).

Contrary to its popularity, chloroquine did not enjoy the same
lengthy period of effectiveness as quinine did (7). It was 12 years after its widespread
use when reports of chloroquine resistance began to appear (8). As shown in
Figure 3, chloroquine resistance currently occurs worldwide, rendering it an
ineffective treatment (3). However, newer drugs have experienced even less
longevity: mefloquine resistance occurred five years after its distribution,
and atovaquone barely saw a year pass by (8).

What gave chloroquine such a
relatively long run is its mechanism of action. Newer compounds target enzymes,
contributing to their rapid ineffectiveness. Chloroquine’s mechanism of action
is unique because it is non-enzymatic (5). Plasmodium
falciparum contains a digestive food vacuole that breaks down hemoglobin as
it grows in our red blood cells. The breakdown product from hemoglobin
digestion is hematin and highly toxic to P.
falciparum. To cope with the toxicity P.
falciparum clumps hematin into harmless crystals and stores them within the
vacuole. Chloroquine disrupts the polymerization process by binding to hematin
and maintaining it in its toxic form,killing the parasite
by accumulation (5). This metabolic pathway appears to be rather complex
because P. falciparum has to undergo
several mutations before resistance is conferred. This complexity appears to be
missing in regard to drugs like pyrimethamine, where resistance is easily
acquired via a single mutation in an enzyme (7).

With drug resistance appearing in newer drugs at a rate
faster than the time invested in researching and developing these agents,
options seem limited. There is a need for new drug targets and new therapies,
and recently significant progress has been made to meet this need.

Drug development can be approached using several tactics. One method is to develop analogs of existing
agents. The benefit is that the relative effectiveness and mechanism is already
known but the slight different can circumvent resistance problems. It was by this method that chloroquine was
synthesized from quinine and subsequently several other quinine-related
compounds such as tafenoquine and the 4-aminoquinolines (5). As an example, a group
of researchers recently focused on quinolones, a compound unique in its ability
to perform inhibitory function in two discrete cell pathways. While inhibiting bc1, a component of cellular
respiration, appropriately structured quinolones can also stack together and
chelate heme, depriving P. falciparum
of both a method of creating energy and obtaining nutrients. From a base
template they developed twenty novel quinolone derivatives that were tested for
effectiveness against P. falciparum
and found a quinolone ester derivative that was highly effective (1).

Finding compounds in the natural environment is another
option. While compounds isolated from natural sources may make it easier to
introduce a treatment to natives, the cost is relatively high compared to other
methods (5). One drug found in this manner is artemisinin. In the 1980s
drug-resistant malaria affecting both sides of the Vietnam War spurred both
China and the United States to develop new effective drugs. Chinese scientists
discovered the compound artemisinin in sweet wormwood, now known in the form of
derivatives such as artemether, arteether, and artesunate (4). Like
chloroquine, this highly effective drug also targets P. falciparum’s food vacuole and stimulates free-radial formation that
inflicts damage to the cell. To this date, P.
falciparum remains sensitive to artemisinin, making it an ideal replacement
for chloroquine use (8).

Until recently a
significant amount of research has focused on the interaction between P. falciparum and humans and as a result
all drugs and agents on the market so far have been developed based on this
relationship. However, the complex lifecycle of P. falciparum makes it possible to study mosquitos as potential
drug targets as well. This is particularly important because mature gametocytes
can persist in a patient’s blood for weeks after alleviation of symptoms, thus
transmission can still occur if a mosquito takes its blood meal in that time
period. Earlier this November a research group reported a class of compounds
that blocks oocyte development in the midgut of the mosquito (2). This halts P. falciparum transmission to a new host
because midgut oocyte development is the precursor of sporozoites (7). These
sporozoites travel to the mosquito salivary glands and infect a person bitten
by that mosquito. Table 4, taken from this paper, shows the effect of several
drugs on oocyte counts in the mosquito midgut. They were able to identify
cyproheptadine and protryptyline as highly effective compounds against midgut
oocyte development and these compounds were also considered safe for humans and
animals. If this research is confirmed and an effective method of distribution
of the compound is elucidated, it will have significant implications in new
methods of P. falciparum control.

Even with all these advances P. falciparum’s ancestral relatedness to us makes it difficult to
identify drug targets that are will not also negatively affect our own cells. In
order to accomplish this an improved understanding of the physiology of P. falciparum is required. Even though
the genome sequence is readily available biochemical and genetic manipulations
are still a limiting factor in ongoing research (5). This adds to the
complexity of developing new drugs and drug targets.

The development of antimalarial
agents gets even more complicated from an economical standpoint. Ironically the
populations who need an effective antimalarial treatment the most are the ones
that have next to no funds to cough up for it. Lack of private investment in
current antimalarial drug development and distribution can be blamed on this
irony. Companies would rather pursue treatments for what I like to call “first
world problems” which guarantee a consumer base that is able to afford the
costs of these treatments (4). Such is not the case for a vast majority of
malaria sufferers worldwide.

Simple economics is the predominant reason why chloroquine
was such an effective treatment. At $0.10 an adult dose and orally ingested,
chloroquine was both affordable and easily administered (4). Currently the danger
with chloroquine is that although ineffective it is still being distributed in
resistant regions of Africa instead of newer and more effective therapies
because of the cost. At its cheapest, even artemisinins are at least ten times
as expensive for consumers as chloroquine. It is estimated that in order to
make artemisinins affordable subsidies of $300 to $500 million a year are
required. If that sounds like a lot of money, it pales in comparison to the
economic burden malaria has in Africa. Lost productivity and investment
revenues due to P. falciparum-related
illness and death amounts to an estimated $3-12 billion a year in the
continental gross domestic product. (4).

Although it is present,
benevolent charity contributions can only go so far. In order to create
incentive for pharmaceuticals and other agencies to develop antimalarials there
has to be a market worth investing in. A report issued by the Institute of
Medicine Committee on Economics of Antimalarial Drugs suggests the $300 to $500
million subsidies mentioned before so artemisinin becomes affordable for
consumers. An additional $10 to $30 million is also recommended for short-term
production stimulation. The idea is that an international organization
purchases the treatment from the producing companies for the competitive market
price, and sells the drug to countries’ governments at the same price
chloroquine is sold, thereby absorbing the cost difference. In return,
countries ensure that the treatment is properly distributed to replace
chloroquine in even the most impoverished regions. If these suggestions are put
into action, it will increase access to effective antimalarials in impoverished
areas. This will allow us to regain control of P. falciparum and alleviate the economical and social burden
malaria has in these endemic regions (4).

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